Preparation of lactic acid derivatives and their use

ABSTRACT

The present invention relates to preparing lactic acid derivatives that are useful as odorants and monomers for polymer synthesis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT/US03/23119 filed Jul. 24, 2003, andpublished as WO 2004/013121 on Feb. 12, 2004.

This application claims priority to U.S. provisional patent applicationNo. 60/400,474, filed Aug. 2, 2002, entitled “Preparation of Lactic AcidDerivatives and Their Use,” by S. A. Selifonov, which is herebyincorporated by reference in its entirety.

TECHNICAL FIELD

The present invention relates to preparing lactic acid derivatives thatare useful as odorants and monomers for polymer synthesis.

BACKGROUND

Certain 3-methyl-1,4-dioxan-2-ones are known to be useful as odorants.

However, there are general problems with preparation of dioxanonecompounds such as associated with use of halogenated raw materials,occurrence of undesired by-products, complexity of synthesis, lowyields, and, subsequently high cost. These problems limit application ofsuch compounds as odorants and make them too expensive for polymersynthesis.

SUMMARY

The present invention provides a novel and versatile method of makingcompounds of formula (1) and (2)

by using lactic acid esters with a free hydroxyl group, and,particularly, ethyl lactate as an inexpensive, safe and abundantrenewable raw material available, for example, by means of fermentationof carbohydrates to lactic acid and to ethanol, followed by chemicalpreparation of the ester. The hydroxyl group of lactate esters issufficiently reactive to provide for opening of various epoxy compounds,thereby yielding a 2(2′-hydroxyethyl)-propionate ester of formula (2).The latter compounds can be used as such in polymer synthesis or can befurther converted to a 3-methyl-1,4-dioxan-2-one via convenienthydrolysis-lactonization sequence or by transesterification. The3-methyl-1,4-dioxan-2-ones are useful as monomers for polymer synthesisand as odorants. Because many epoxides are produced on a large scale orcan be readily prepared by various oxidation methods from a greatvariety of olefinic compounds, such method is particularly useful andversatile to provide for a library of novel odorant compounds andmonomers for polymer synthesis. The type of scent greatly depends on thestructure of the epoxide used in the synthesis. Similarly, theproperties of polymers or co-polymers depend on the structure of theepoxide. Versatility of the synthetic method of the present inventionallows for fine tuning of the desired target properties of the resultingodorants or polymers.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims.

DETAILED DESCRIPTION

2(2′-hydroxyethyl)-propionate esters (2) can be conveniently andeconomically prepared by reaction between an epoxide and a lactate esteraccording to the following reaction in Scheme 1:

wherein R₁, R₂, R₃ are each independently H, straight or branched alkylgroup, straight or branched alkenyl group, carboxyalkyl, carboxyaryl,aromatic group, aromatic-aliphatic group, alkyloxyalkyl, aryloxyalkyl,cycloalkyl, cycloalkenyl, or oxacycloalkyl, or wherein any two of R₁,R₂, and R₃ can form a ring containing 5 to 15 carbon atoms, and whereinany of R₁, R₂, or R₃ optionally contain one oxygen-functional groupselected from hydroxyl, carbonyl or protected forms thereof and

wherein R₄ is a group having between 1 and 50 carbon atoms selected fromthe group consisting of straight or branched alkyl groups, straight orbranched alkenyl groups, cycloalkyl or cycloalkenyl groups,alkyloxyalkyl groups, aromatic groups, aromatic-aliphatic groups,hydroxy-functional alkyl groups, and combinations thereof, or a polymerchain comprising one or more ester or ether, amide bonds.

General conditions useful for a broad range of epoxide opening reactionswith lactate esters are described. Such conditions include the use ofvarious catalysts. Typically, such catalysts include various acids.Examples include strong mineral acids, such as sulfuric, hydrochloric,and hydrobromic acids, p-toluenesulfonic acid, camphorosulfonic acid,methanesulfonic acid and the like. Various resins that containprotonated sulfonic acid groups are also useful as they can be easilyrecovered after completion of the reaction. Boron trifluoride andvarious complexes of BF₃, e.g., in the form of BF₃ dietherate, are alsouseful. Silica, acidic alumina, titania, zirconia and various acidicclays can also be used. However, the nature and amount of the catalystis not critical. Elevated temperatures may be used to accelerate thereaction with less reactive catalysts, however, the temperature of thereaction mixture is not critical. The amount and type of catalystdepends on the specific chemical composition of the epoxide and lactateester taken for the reaction and can be readily established by oneskilled in the art.

Various co-solvents can be used for the reaction of epoxides with thelactate ester. When co-solvents are used, it is preferred that thesolvent not contain a significant amount of water, alcohols, amines,thiols or carboxyl compounds so that competing reactions do not giverise to undesired side products. Various aliphatic and aromatichydrocarbons, ethers, and esters, including chlorinated compounds, canbe used. The use of a co-solvent is particularly beneficial when solidor highly viscous epoxides or lactate esters are used in the synthesis.

To minimize formation of side products, it is advantageous to conductthe reaction between an epoxide and a lactate ester in the presence ofsufficient excess of lactate ester, typically with molar ratio ofepoxide to lactate ester being in the range of between 1:1.1 to 1:1000,more preferably from 1:1.5 to 1:50. In practice such is easilyaccomplished by a gradual addition of epoxide to a liquid lactate ester(4), or a mixture of the latter and a suitable co-solvent, and carryingout the reaction until substantially all epoxide has reacted, therebyyielding a mixture of lactate ester (4) and the desired2(2′-hydroxyethyl)-propionate ester. After reaction, the residuallactate ester can be conveniently distilled out of the higher boiling2(2′-hydroxyethyl)-propionate ester (1) and reused. The distillation ofexcess lactate ester is typically carried out at atmospheric pressure orunder reduced pressure. Distillations under reduced pressure arepreferred because they minimize thermal stress to the reaction productsand mitigate formation of side products due to elimination reactions ortransesterification.

Any number of lactic acid esters of formula (4) can be used for reactionwith epoxides. In a preferred embodiment, use of lower alkyl esters isadvantageous because of low cost, high purity and safety, as well asconvenience of product separation and re-use of excess of alkyl lactate.In particular, linear or branched alkyl esters of lactate with alcoholshaving 1–6 carbon atoms are preferred, and ethyl lactate is the mostpreferred. Both enantiomers of lactate esters can be used in thereaction with epoxides. Racemic or enantiomerically enriched lactatescan be used. Use of the (S)-enantiomer of lactate esters, and inparticular the (S)-enantiomer of ethyl lactate with enantiomeric purityin excess of 80% is preferred due to low cost and ample availability.

Any number of epoxides of formula (3) can be used. Many epoxides areavailable commercially in great quantity at low cost. Various methodscan be used to prepare epoxides. Olefins can be epoxidized with variousreagents, such as peracids and their salts, alkylperoxides, hydrogenperoxide, oxygen, or by the halohydrin method. Various catalysts can beused for epoxidation, including enantioselective or regioselectivereactions. Enzymatic or microbiological methods can be used to preparecertain epoxides, and enantiomerically enriched chiral epoxides inparticular. For example, styrene monooxygenase or xylene monooxygenasecan be used to prepare styrene 1,2-epoxide. Alkane monooxygenase can beused to prepare epoxides from a range of straight chain and branchedalkenes, such as 1-hexene, 1-heptene, 1-octene, 1-nonene and like.

The following non-limiting examples of epoxy compounds are provided forthe purpose of illustration.

Examples of epoxides include epoxides of linear or branched alkenes,such as ethylene oxide, propylene 1,2-oxide, butylene-1,2- or 2,3-oxide,and 1,2-epoxides of individual or mixed alpha olefins having 5–20 carbonatoms.

Further examples of epoxides include 1,2-epoxides of cyclic alkenes andalkylated cyclic alkenes such as cyclopentene, cyclohexene, cyclooctene,cyclododecene rings, and the like.

Further examples of epoxides include mono- and diepoxy compounds ofconjugated and non-conjugated dienes and trienes such as butadiene,isoprene, 1,3- and 1,4-cyclohexadienes, cycloheptatriene,1,5,9-cyclododecatriene, 1,5-cyclooctadiene,dimethyl-1,5-cyclooctadiene, 4-vinyl-1,2-epoxycyclohexene,norbornene-2,3-oxide, epoxydicyclopentadiene, and the like.

Additional examples of epoxides include epoxides of aromatic alkenessuch as styrene-1,2-oxide, indene-1,2-oxide,3,4-dihydronaphthalene-1,2-oxide, allyl benzene 2,3-oxide, and the like.

Epoxides can be obtained from many natural and synthetic terpenes andterpenoid compounds. Examples of epoxides of this type includelimonene-1,2-oxide, 1-menthene-1,2-oxide, 2-menthene-2,3-oxide,isolimonene-2,3-oxide, epoxides of alpha- and beta-phellandrenes, alpha-and beta-pinenes, 2- and 3-carenes, myrcene, ocimene isomers, alpha andgamma terpinenes, and camphene, as well as epoxides of oxygenatedterpenoids, such as geraniol, nerol, linalool, terpineol, terpinhydrate, and their esters and ethers, carvone, carveol isomers,piperitol, isopiperitenol, and the like.

It is not necessary to always have epoxides of high purity or definedcomposition. For example, crude or rectified essential oils or theirfractions can be epoxidized to produce a mixture of epoxides. Inaddition, fractions from the processing of turpentine that contain mixedunsaturated compounds can be epoxidized and used for reaction withlactic acid esters. Other suitable examples include epoxidized materialsderived from, or comprising, plant essential oils such as spearmint oil,orange oil, lemon oil, grapefruit oil, cedar oil, vetiver oil, bergamotoil, citronella oil, and the like.

Further examples of epoxides include epoxides from olefins havingadditional heteroatoms and functional groups. Examples of thesecompounds include glycidol esters and ethers, as well as epoxides thatcan be prepared by epoxidation of esters and ethers of unsaturatedalcohols. Examples of the latter are epoxides of 2- and 3-hexenol estersand t-butyl ethers. Examples of epoxy compounds having a carboxyl groupare glycidic esters such as epoxyacrylate esters, 2,3-epoxycrotonateesters and like. Another set of examples includes epoxides ofunsaturated ketones, aldehydes and their ketals or acetals.

Epoxides of conjugated cyclic and acyclic unsaturated ketones andaldehydes, with the carbonyl group optionally protected a ketal or anacetal are particularly useful since they can be readily prepared viaaldol condensation of corresponding ketones and aldehydes, followed byepoxidation.

It is also possible for the epoxide and lactate ester to be part of thesame molecule, in which case the reaction between the epoxide moiety andthe hydroxyl group of the lactate moiety can be carried outintra-molecularly, inter-molecularly, or both, depending on reactionconditions. Thus other examples of compounds are esters of lactic acidand unsaturated alcohols such as 2-alkene-1-ols, and of allyl alcohol inparticular. Allyl lactate can be readily prepared from other lactic acidesters by transesterification. For example, transesterification of ethyllactate, or lactate cyclic dimer (lactide,2,6-dimethyl-1,4-dioxane-2,5-dione), or polylactate with allyl alcoholin the presence of sodium or potassium alkoxide can be used to produceallyl lactate. The latter can be epoxidized to yield glycidol lactate,which can react intramolecularly to produce3-methyl-5-hydroxymethyl-1,4-dioxan-2-one (and/or an isomeric cycliccompound 4-oxa-3-methyl-6-hydroxy-ε-caprolactone) or inter-molecularlyto produce oligomeric or polymeric products.

Compounds of formula (2) can be used to prepare the3-methyl-1,4-dioxan-2-one compounds having formula (1). The2(2′-hydroxyethyl)-propionate esters of formula (2) resulting fromreaction between an epoxide and a lactate ester can be readily convertedto the cyclic ester by one of several methods shown in Scheme 2.

Method (A) comprises two separate reactions. First, the ester of formula(2) is hydrolyzed (saponified) in the presence of sufficient amount of abase, thereby yielding a salt of the 2(2′-hydroxyethyl)-propionate (6),or a mixture of the said salt and free acid (5). Typically, suchreaction will be performed by addition of an aqueous solution of analkali metal hydroxide or an alkali-earth metal hydroxide. Examplesinclude sodium hydroxide, potassium hydroxide, calcium hydroxide, andthe like. Sodium hydroxide in water or calcium hydroxide in water arethe preferred reagents. After saponification, the reaction mixture isacidified by addition of a sufficient amount of strong acid. Mineralacids such as hydrochloric acid and sulfuric acid are preferred due tolow cost. Such acidification results in the formation of the desired the3-methyl-1,4-dioxan-2-one of formula (1). The compound can be isolatedfrom the reaction mixture by extraction with appropriate solvent orsimply by phase separation.

Preparation of compound (1) by such method results in the formation offree alcohol R₄OH which can be recovered from the reaction mixture,typically by distillation or extraction. The alcohol can subsequently bere-used for preparation of lactic acid ester of formula (4) by atrans-esterification of lactide, or of polylactate, or of other lactateester, thereby reducing cost of preparation of3-methyl-1,4-dioxan-2-ones on the industrial scale.

Method (B) is a variation wherein hydrolysis of the compound (2) iscarried out by an enzyme, typically by a lipase or esterase. Manyenzymes of this type are known and available in commercial quantities.Free or immobilized enzymes can be used. The reaction can be carried outin the presence of a suitable co-solvent. The nature of the enzyme isnot critical, and many methods in the art are known that allow forimprovement of enzyme performance under specific reaction conditionsthat may be tailored for the specific composition of compound (1).Depending on the precise conditions used, 3-methyl-1,4-dioxan-2-ones canbe formed with or without formation of appreciable amounts of the free2(2′-hydroxyethyl)-propionic acid. Sufficiently thermostable lipases andesterases are preferred as their use allows for continuous distillationof alcohol R₄OH at atmospheric pressure, as such alcohol is formedduring the course of reaction.

Method (C) is a variation wherein an internal transesterification iscarried out in the presence of catalytic amounts of acid, borontrifluoride, strong base, or alkali metal alkoxide, and in the absenceof appreciable amounts of water or other compounds having free hydroxylgroups. Such reaction typically is carried out at elevated temperaturesthat are sufficient to distill off the alcohol R₄OH from a mixture ofcompounds (1) and (2), or at room temperatures, when removal of alcoholR₄OH during the transesterification is not desired. Appropriateco-solvents can be used to minimize formation of by-products such asoligomers and polymers. Typical examples of such co-solvents includehydrocarbons or ethers. When method (C) is carried out in the presenceof acid or boron trifluoride catalyst, the internal transesterificationresulting in the formation of dioxanone (1) can be conductedcontemporaneously with the reaction between the epoxide (3) and theester (4) shown in the Scheme 1, and without isolation of intermediatecompound (2).

Method (D) is a variation wherein the 2(2′-hydroxyethyl)-propionic acidester (2) or free acid (5) is dehydrated under sufficiently acidicconditions and elevated temperatures to yield a compound of formula (7)or a free acid (8). The latter is readily cyclized to yield compoundhaving formula 1. Such method is particularly useful for epoxides ofcyclic compounds, and, in particular, for compounds where both R₂ and R₃are not hydrogens, and at least one of R₂ and R₃ has a hydrogen atomcapable of elimination under acidic conditions. Depending on theseverity of the treatment of compound (2) with acid, and the nature ofthe epoxide and enantiomeric composition of the lactic ester, suchmethod provides for changes in relative stereoisomeric composition ofthe resulting cyclic dioxanone of formula (1) at the carbon atom bearingR₂ and R₃ in particular.

Any of the methods (A), (B), (C), or (D) are practically useful and canbe successfully practiced in a continuous operation mode. Methods (B),(C), and (D) are preferred because such methods do not produce largeamounts of inorganic salt by-products.

Method A is preferred in the cases where it is desired to obtain aquantity of pure dioxanone material substantially free of esteroligomers, typically represented by linear or cyclic ester oligomers ofcompounds (1) and (2) with the lactic acid.

As it will be apparent from the examples provided herein below, variousquantities of cyclic and/or linear by-product oligomers, comprisingesterified fragments of compound (2), are formed during reaction ofepoxide (3) with ester (4) and/or during subsequent cyclization reactionleading to compounds of formula (1). The amount and composition of sucholigomers depends on the specific conditions employed to obtaincompounds (1) and (2), and on the specific structures of epoxide (3) and(4). Typically, when stronger catalyst or increased amount of catalyst,or elevated temperatures or prolonged reaction times are used forreacting compounds (3) and (4), and/or to accomplish conversion of (2)to (1), the amounts of the oligomeric ester products comprising esterfragments of compound (2) are higher. However, if and when anyappreciable amounts of such oligomers are formed during synthesis ofcompounds (1) and (2) by methods described herein, such oligomers arealso useful compounds for perfumery, flavor, and polymer applications.Such oligomers can be optionally separated from the dioxanones (1)and/or from hydroxyesters (2), and converted to the dioxanones usingtransesterification or saponification-lactonization procedures describedherein. Alternatively, a mixture comprising compounds (1) and/or (2) andvarious amounts of cyclic or linear oligomers, can be saponified andthen acidified to obtain pure practically pure dioxanones (1).

Another embodiment of the present invention comprises the synthesis ofcompounds of formula (1) and (2) with epoxides possessing additionalhydroxyl groups or optionally protected hydroxyl groups, typicallylocated in a vicinal position to the epoxy group, e.g., epoxides ofallylic alcohols or glycidol derivatives. This embodiment is exemplifiedby the reactions shown in Scheme 3, wherein R₆ is H or a protectiongroup selected from ketal, acetal, 2-tetrahydropyranyl,2-terahydrofuranyl, tertiary branched or cyclic alkyl, carboxylic ester,or silyl group having 3 substituents selected from linear or branchedalkyl, aryl, and arylalkyl groups.

In this embodiment, where both R₂ and R₃ are not H, the dioxanone ringis preferentially formed with an oxygen atom at the adjacent carbon atomposition (compound 1a), and the latter compound can be optionallydehydrated to dioxanone (1b) having a double bond in the side chain atthe position C-6. When one of R₂ and R₃ or both are H, the resultingdioxanone product is a mixture of product isomers exemplified by theformulae (1a) and (1c):

Compounds of general formula (1) prepared from racemic epoxides havingchiral centers are typically formed as mixtures of stereoisomers, and,in particular, as mixtures of 3,6-cis and 3,6-trans isomers. Suchmixtures of isomers can be used in applications described below, or canbe separated, if desired, to obtain substantially pure isomers orcompositions with an increased (enriched) amount of one isomer. Methodsfor resolution of such isomeric mixtures include fractional distillationand biocatalysis using one or more of ordinary esterases or lipasesknown in the art. Such enzymes typically display moderate to highselectivity under reaction conditions that include or excludesubstantial amounts of water from reactions, and can be carried out in abroad range of solvents under conditions that favor hydrolysis,alcohololysis, or transesterification. A compendium of methods for usingesterases and lipases for stereoisomer resolution can be found in thetextbook by K. Faber (1995, Biotransformations in Organic Chemistry,Spinger-Verlag, ISBN 3-540-58503-6).

Many compounds of formula (1) with total number of carbon atoms lessthan about 25 have attractive scent characteristics. Depending on thenature of epoxide (5) and the enantiomeric composition of lactic acidester (4), various types scents of various tenacity can be obtained. Arange of scents represented by compounds of formula (1) includescompounds with notes that can be described as floral, fruity, peach,oily, woody, amber, citrus, minty, and cooling. Individual compoundshaving formula (1) or their mixtures can be used as odorant compounds invarious perfumes, hair care products (e.g., shampoos, styling creams,and the like), cosmetics (e.g., lipstick, face powder, and the like),laundry powders, deodorants, candles, air fresheners, soaps, dental careproducts, cleaning formulations and the like. They can also be used asartificial flavors to impart original taste characteristics in softdrinks, processed fruit products, dairy products such as yogurts,chewing gum, candies, baked goods, tobacco, mouthwash, and the like.

The olfactorily effective amount for a particular dioxanone of formula(1) depends on the precise structure of groups R₁, R₂, R₃, and thestereoisomeric composition of the dioxanone. The potency of the scentand taste can be readily determined by one of ordinary skill in the artby examination of various dilutions of the dioxanone or variousconcentrations of vapor in the air sample. Such examination can be usedas a guide to establish optimal amounts of the dioxanone in a particularfragrance, flavor composition, or formulation.

Compounds of formula (1) and formula (2) can be used to prepare a rangeof polyester polymers. Such compounds can be used as individualcompounds in substantially pure form, or as mixtures of compounds,wherein a mixture is represented by compounds prepared from differentepoxides and/or from different enantiomers of lactic esters, and/or fromdifferent isomers resulting from alternative nucleophilic opening of theepoxide at carbon atoms bearing either R₁ or R₂, where applicable.Compounds (1) and (2) can be used as co-monomers with other compoundscapable of forming polyester polymers. Non-limiting examples ofco-polymers of compounds (1) and (2) include those copolymers thatcomprise ester fragments derived from lactic acid, glycolic acid, andother 2-hydroxyacids, from 4-hydroxybutyric acid, p-, m-,o-hydroxybenzoic acids, 6-hydroxy-2-naphthoic acid, various aminoacids,as well as combinations of dicarboxylic acids and glycols. Becausecompounds (1) and (2) can be prepared from a range of epoxides, theprecise properties of the resulting polymer can be influenced to a greatextent by selection of the particular epoxide used to prepare thecompounds. Dioxanones (1) derived from epoxides from alpha-olefins,styrene, allylbenzene or from various glycidyl ethers, offer thegreatest flexibility in the precise control of polymer and co-polymerproperties, including such properties as melting and softeningtemperatures, crystallinity, mechanical properties (such as elasticity,stretch/torsion/break resistance), dyeability, hydrophobicity andhydrophilicity, biodegradability, plasticizing properties, metalchelating properties, detergent properties, coagulation and waterclarification properties, solvent resistance and solvent swelling,adhesive properties, blending compatibility, and the like.

Methods for preparation of polyesters from carboxylic hydroxyacids,diacids and alcohols, as well as from their esters or lactones, are wellknown in the art. Such methods are generally applicable to the compounds(1) and (2), and can be used by one skilled in the art withoutsubstantial modifications. For example, polymerization of compounds offormulae (1) and (2), and any oligomeric esters thereof, can beaccomplished using transesterification under acidic or alkalineconditions, typically under temperatures that allow for distilling outthe alcohol R₄OH and/or any water that may be present or formed duringthe polymerization reaction. The polymerization can be accomplishedusing a variety of other catalysts, such as transition metal salts ofalkanoic acids exemplified by tin 2-ethylhexyloctanoate. Polymerizationand co-polymerization of dioxanones of formula (1) can be alsoaccomplished by methods and catalysts described by K. Bechtold, M. A.Hillmyer, and W. B. Tolman. (Macromolecules 2001, 34, 8641–8648), and inreferences cited therein, for preparation ofpoly-3-methyl-1,4-dioxan-2-one.

Mixtures of dioxanones (1), hydroxyesters (2), and any ester derivativesthereof that have been obtained by reaction of compounds (3) and (4) canbe polymerized to useful co-polymers with lactic acid directly andwithout separating excess lactic acid ester (4). In this embodiment, theratio between lactate fragments and 2(2′-hydroxyethyl)-propionate esterfragments derived from dioxanone (1) or hydroxyester (2) dependssubstantially on the ratio between epoxide (3) and lactic ester (4) usedin the reaction leading to the formation of the ether bond between thelatter two compounds.

Compounds (1) and (2) can also be co-polymerized with lactide(3,6-dimethyl-1,4-dioxan-2,5-dione) and/or with glycolide(1,4-dioxan-2,5-dione), and/or with 3-methyl-1,4-dioxan-2,5-and/or withtartaric or mesotartaric acid or esters thereof, or graft co-polymerizedwith polylactic acid, or with polyglycolic acid or withlactate-glycolate copolymers, or with other polymers.

Compounds (1) and (2), and compound (9), described below, and anymixtures thereof, and any ester derivatives or oligomers or polymerscomprising fragments of these compounds, can also be polymerized orco-polymerized with other polymers or monomers by using lipases oresterases. Methods for using such enzymes in polyester synthesis andmodifications are well known in the art. A description of generalenzyme-based polymerization, depolymerization and trans-polymerizationmethods can be found, for example, in the articles by Gross R. A. et al,(2001, Appl Microbiol Biotechnol. Jun;55(6):655–60), Deng F, and Gross RA. (1999, Int J Biol Macromol. 25(1–3):153–9, Kumar A, and Gross R A.(2000, Biomacromolecules. Spring, 1(1):133–8), Ebata H, et al (2000,Biomacromolecules. Winter;1(4):511–4); Kobayashi S, et al, (2000,Biomacromolecules. Spring;1(1):3–5), Namekawa S. et al. (2000,Biomacromolecules. Fall;1(3):335–8), Namekawa S et al., (1999, Int JBiol Macromol. Jun–Jul, 25(1–3):145–51), and in the references citedtherein.

Useful polymers can also be prepared by reacting epoxide (3) andhydroxyester (4) in the compound ratio that favors formation of productsof the general formula (9):

wherein m is an integer having value from 1 to about 50.

Preparation of such compounds is typically accomplished by using a ratiobetween compounds (3) and (4) in the range from about 50:1 to about 1:1.Preparation of such compounds is typically accompanied bycontemporaneous preparation of compounds of formulae (1) and (2).Compounds of formula (9) can be used as co-polymers in the preparationof many polyester-polyether co-polymers that are similar in principalproperties to many poly(epoxides) known in the art, and possessadditional advantages, in particular, due to the presence of ester bondsin the polyether backbone, such as improved biodegradability in theenvironment, as compared to poly(epoxides) having continuous polyetherbackbone uninterrupted by ester bonds.

Polymers and co-polymers comprising fragments of compounds (1), (2) or(9) are also useful for preparing various blends, alloys, or compositeswith inorganic materials, plasticizers, or with other polymers. Inparticular, blends and alloys comprising, on one hand, a polymerselected from polylactic acid, polyglycolic acid, or co-polymerscomprising fragments of lactic acid, glycolic acid, orpoly-(3-hydroxybutyrate) and, on the other hand, polyesters, polyamides,polyepoxides, polyolefins, polystyrene, polyacrylates,polymethacrylates, and polysaccharides, can be prepared by providingfragments of compounds (1), (2), or (9) in at least one polymer orco-polymer. Such blends have improved characteristics and aresubstantially devoid of phase separation problems, for example, phaseseparation problems in blends of polylactic acid with polyethylene,polypropylene, or polystyrene

EXAMPLE 1

0.05 ml of racemic styrene epoxide was rapidly added to a solution of 1microliter of boron trifluoride dietherate in 1 ml of ethyl S(−)lactateand the whole was stirred for 2 minutes at room temperature (about 25°C.). An aliquot (0.01 ml) of the resulting reaction mixture was takenand diluted with ethyl acetate, and was immediately analyzed by GC-MSand GC-FID. The analysis showed complete conversion of styrene oxide toseveral products. Approximately equal amounts of 3,6-cis-(syn-) and3,6-trans-(anti-) isomers of 6-phenyl-3-methyl-1,4-dioxan-2-one isomers(formulae 11a and 11b) accounted for about 81% of the reaction products.The percentage number excludes from the calculation, herein and in thesubsequent examples, the excess of ethyl lactate used in the reaction;the percentage numbers provided are an approximate indication of yieldbased on styrene oxide.

The isomers of 6-phenyl-3-methyl-1,4-dioxane-2-one had the followingmass-spectra electron ionization mass-spectra at 70 eV, m/z (%abundance):

Trans-isomer (11a):

192 (20, M⁺), 162 (8), 133 (9), 119 (3), 104 (100), 91 (21), 77 (16), 65(4), 56 (35).

Cis-isomer (11b):

192 (8, M⁺), 162 (5), 133 (6), 119 (2), 104 (100), 91 (18), 77 (15), 65(4), 56 (32).

Approximately 9% of the products were represented by two diastereomersof the hydroxyacid ethyl esters of formula (12):

About 3% of the products were represented by cyclic and linear isomersof formulae (13) and (14):

About 2% of the products were represented by a cyclic dioxanone dimer offormula (15):

GC analysis of the same reaction mixture after incubation at roomtemperature for up to 2 hours with stirring at room temperature showedgradually increased amounts of compounds (13) and (14) due totransesterification reactions in the presence of boron trifluorideetherate, and correspondingly decreased amounts of dioxanones (11a, 11b)and hydroxyesters (12).

EXAMPLE 2

The synthesis was carried out as in example 1, except hexene-1,2-oxidewas used instead of styrene oxide. The GC analysis showed completeconversion of hexene 1,2-oxide. Dioxanone isomers having formulae (16a)and 16b) accounted for about 47% of the product mixture. Hydroxyestersof formula (17) accounted for about 32% of the product mixture.Ester-acetal of formula (18) accounted for 9% of the product mixture.

The mass spectrum of dioxanone compound (16a) had a molecular ion withm/z (% abundance) of 172 (13), and characteristic fragment ions 143 (1),129 (7), 113 (1), 99 (2), 84 (83), 69 (30), 56 (100), 43 (32). The massspectrum of dioxanone compound (16b) was very similar except themolecular ion was less intense (about 5% of the base peak with m/z 56).

EXAMPLE 3

The synthesis was carried out as in example 1, exceptcycloxene-1,2-oxide was used instead of styrene oxide. The GC analysisshowed complete conversion of cyclohexene 1,2-oxide and the formation ofabout equal amounts of two isomers of4-methyl-2,5-dioxabicyclo-[4,4,0]-decan-3-one having formulae (19a) and(19b) that accounted for about 65% of reaction products formed:

These compounds had very similar mass-spectra characterized by molecularion with m/z (% abundance) of 170 (6), and a series of fragment ions 141(0.3), 126 (5), 108 (0.5), 98 (5), 82 (85), 67 (100), 54 (31), 41 (21).

The remainder of the product comprised several isomers of compoundshaving formulae (20), (21) and (22):

EXAMPLE 4

The synthesis was carried out as in example 1, except allyl glycidylether was used instead of styrene oxide. The product mixture containedabout 20% of dioxanone isomers of formula (23)

EXAMPLE 5

The synthesis was carried out as in example 1, except cyclopentene1,2-oxide was used instead of styrene oxide.

The product mixture contained about 1.5% each of two dioxanone isomershaving general formula (24):

wherein the wiggled bonds are in a trans-configuration to each other.

The mass-spectra of both isomers of dioxanone (24) had a low intensitymolecular ion with m/z (% abundance) 156 (0.5), and fragment peaks withm/z 94 (8), 83 (6), 81 (7), 68 (100), 55 (22), 45 (15).

The product mixture was found to contain predominantly hydroxyesters offormulae (25a) and (25b) in approximately equal amounts, accounting forabout 89% of the reaction products:

Approximately 6% of the reaction products were represented by oligomericand cyclic oligomeric compounds having formulae (26), (27), (28):

EXAMPLE 6

The synthesis was carried out as in example 1, except p-nitrophenylglycidyl ether was used instead of styrene-1,2-oxide and the borontrifluoride dietherate amount was 0.3 microliters. After 5 minutes, thereaction mixture was found to contain about 38% of the initially addedamount of p-nitrophenyl glycidyl ether (ca. 62% epoxide conversion). Theproducts found in the reaction mixture comprised about 27% each of twomajor isomers of dioxanones having formulae (29a) and (29b), and about2% each of two minor isomers of dioxanones having formulae (29c) and(29d):

The dioxanones of formulae (29a) through (29d) had very similar massspectra characterized by high intensity molecular ion. For example,dioxanone of formula (29a) was found to have a molecular ion with m/z (%abundance) of 267 (100), and a series of fragment ions 250 (5), 237 (5),224 (0.5), 207 (0.5), 195 (0.5), 179 (31), 162 (11), 152 (9), 132 (4),122 (5), 109 (5), 101 (10), 87 (33), 76 (9), 59 (19), 57 (18), 41 (48).

EXAMPLE 7

2 g of DOWEX-50W (strongly acidic cation-exchange resin, protonatedform, pre-washed with ethyl lactate) were added to 50 ml of ethyllactate, and 5.16 g of styrene oxide were added dropwise over 15 minutesto the suspension. The whole was stirred by means of magnetic stirrerfor 1 hr at 25° C. After that, the reaction mixture was heated at 55° C.for 3 hours with stirring, cooled to room temperature, filtered, andanalyzed by GC-MS and GC-FID. The analysis showed complete conversion ofstyrene oxide into several products that comprised about 76% of 1:1mixture of 3,6-syn- and 3,6-anti-isomers of6-phenyl-3-methyl-1,4-dioxan-2-one (11a and 11b), about 6% ofhydroxyesters (12), about 1% of ester ketal having formula (30),

about 2 (%) of ester acetal having formula (31),

and about 11% of linear and cyclic esters of formulae (13) and (14).

Approximately 42 ml of practically pure ethyl lactate was distilled outthe reaction mixture by heating to about 160° C. at atmosphericpressure. The remaining pale yellow viscous liquid was saponified with30 ml of 20% sodium hydroxide in water by heating for 2 hours at 95° C.with stirring. The resulting solution was cooled to room temperature,washed 3 times with 20 ml of methyl tert-butyl ether, and filtered. Thefiltered solution was acidified, while being maintained on the ice bath(4–5° C.) and stirred, by dropwise addition of 20% sulfuric acid inwater until pH about 2–3 was reached. The acidified solution wasextracted 4 times with 30 ml of ethyl acetate, the extracts werecombined, dried over anhydrous sodium sulfate, and the solvent wasremoved under reduced pressure, to yield 7.60 g of pale-yellow clearoil. The crude product was analyzed by GC-MS and GC-FID and found tocontain about 80% of 1:1 mixture of 3,6-syn- and 3,6-anti-isomers of6-phenyl-3-methyl-1,4-dioxan-2-one (11a and 11b), and about 20% of thecyclic dimer product having formula (15).

An analytical sample of practically pure 3,6-syn- and 3,6-anti-isomersof 6-phenyl-3-methyl-1,4-dioxan-2-one of 1:1 mixture was prepared byvacuum distillation. The mixture of syn- andanti-6-phenyl-3-methyl-1,4-dioxan-2-ones was found to possess a powerfuland tenacious unusual floral-honey-rose-balsamic-sweet scent with a noteof pleasant bitterness.

EXAMPLE 8

The synthesis was carried out as in example 7, except 5.1 g of hexene1,2-oxide was used instead of styrene 1,2-oxide. The synthesis yieldedabout 6.2 g of clear colorless oil that was found to contain about 92%of dioxanones of formula (16a) and (16b). The mixture of compounds hadan oily-fruity odor reminiscent of peach.

EXAMPLE 9

The synthesis was carried out as in example 7, except 5.05 g ofcyclohexene-1,2-oxide was used instead of styrene 1,2-oxide. Thesynthesis yielded about 6.9 g of clear colorless oil that was found tocontain about 96% of dioxanones (19a) and (19b), and about 2% of isomersof cyclic esters of formula (32):

The resulting material is found to have a characteristic powerful floralodor reminiscent of castoreum flower.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. A method for making a compound having the formula:

wherein R₁, R₂, R₃ are each independently H, straight or branched alkylgroup, straight or branched alkenyl group, carboxyalkyl, carboxyaryl,aromatic group, aromatic-aliphatic group, alkyloxyalkyl, aryloxyalkyl,cycloalkyl, cycloalkenyl, or oxacycloalkyl or wherein any two of R₁, R₂,and R₃ can form a ring containing 5 to 15 carbon atoms, and wherein anyof R₁, R₂, or R₃ optionally contain one oxygen-functional group selectedfrom hydroxyl, carbonyl or protected forms thereof, and wherein R₄ is agroup having between 1 and 50 carbon atoms selected from the groupconsisting of straight or branched alkyl groups, straight or branchedalkenyl groups, cycloalkyl or cycloalkenyl groups, alkyloxyalkyl groups,aromatic groups, aromatic-aliphatic groups, hydroxy-functional alkylgroups, and combinations thereof or a polymer chain comprising one ormore ester or ether, or amide bonds, said method comprising: a)providing an epoxide of formula (3):

and b) reacting the epoxide with a lactic acid ester of formula (3):

where the epoxide and ester are in the form of separate molecules orpart of the same molecule, thereby providing the compound of formula(2).
 2. A method of claim 1 wherein the reaction between the epoxide andthe lactic acid ester is carried out in the presence of a catalystselected from the group comprising boron trifluoride catalysts, acidcatalysts, and combinations thereof.
 3. A method of claim 1 wherein thereaction between the epoxide and the lactic acid ester is carried out inthe presence of excess lactic acid ester, with the molar ratio betweenthe epoxide and the ester being between approximately 1:1.1 to 1:1000.4. A method of claim 1 wherein the lactic acid ester is glycidyllactate.
 5. A method of claim 1 wherein the reaction between the epoxideand the lactic acid ester is conducted in the presence of a co-solvent.6. A method of claim 1 further comprising cyclizing the compound offormula (2) to produce a compound having the formula:

wherein R₁, R₂, R₃ are each independently H, straight or branched alkylgroup, straight or branched alkenyl group, carboxyalkyl, carboxyarylaromatic group, aromatic-aliphatic group, alkyloxyalkyl, aryloxyalkyl,cycloalkyl, cycloalkenyl, or oxacycloalkyl, or wherein any two of R₁,R₂, and R₃ can form a ring containing 5 to 15 carbon atoms, and whereinany of R₁, R₂, or R₃ optionally contain one oxygen-functional groupselected from hydroxyl carbonyl or protected forms thereof.
 7. A methodas claimed in claim 6, wherein cyclization is carried out by saponifyingthe 2-(2′-hydroxyethyl)propionate ester of formula (2), followed byacidification.
 8. A method as claimed in claim 6 wherein cyclization iscarried out by transesterifying the 2-(2′-hydroxyethyl)propionate esterof formula (2) in the presence of a catalyst.
 9. A method as claimed inclaim 8 wherein cyclization is carried out by treating the2-(2′-hydroxyethyl)propionate ester with catalyst acid or borontrifluoride to eliminate water, followed by hydrolysis of the ester andacidification.
 10. A method of claim 1 wherein the compound of formula(2) cyclizes in situ to form a compound having the formula:

wherein R₁, R₂, R₃ are each independently H, straight or branched alkylgroup, straight or branched alkenyl group, carboxyalkyl, carboxyarylaromatic group, aromatic-aliphatic group, alkyloxyalkyl, aryloxyalkyl,cycloalkyl, cycloalkenyl, or oxacycloalkyl, or wherein any two of R₁,and R₂, and R₃ can form a ring containing 5 to 15 carbon atoms, andwherein any of R₁, R₂, or R₃ optionally contain one oxygen-functionalgroup selected from hydroxyl carbonyl or protected forms thereof.
 11. Amethod as claimed in claim 6 wherein cyclization is carried out byexposing the 2-(2′-hydroxyethyl)propionate ester to an enzyme selectedfrom the group consisting of lipases, esterases, and combinationsthereof.
 12. A compound having the formula:

wherein R₁, R₂, R₃ are each independently H, straight or branched alkylgroup, straight or branched alkenyl group, carboxyalkyl, carboxyaryl,aromatic group, aromatic-aliphatic group, alkyloxyalkyl, aryloxyalkyl,cycloalkyl, cycloalkenyl, oxacycloalkyl, or wherein any two of R₁, R₂,and R₃ form a ring containing 5 to 15 carbon atoms, and wherein any ofR₁, R₂, or R₃ optionally contain one oxygen-functional group selectedfrom hydroxyl, carbonyl or protected forms thereof, and wherein R₄hydrogen or a group having between 1 and 50 carbon atoms selected fromthe group consisting of straight or branched alkyl groups, straight orbranched alkenyl groups, cycloalkyl or cycloalkenyl groups,alkyloxyalkyl groups, aromatic groups, aromatic-aliphatic groups,hydroxy-functional alkyl groups, and combinations thereof, or a polymerchain comprising one or more ester or ether, or amide bonds.
 13. Acompound having the formula:

wherein R₁, R₂, R₃ are each independently H, straight or branched alkylgroup, straight or branched alkenyl group, carboxyalkyl, carboxyarylaromatic group, aromatic-aliphatic group, alkyloxyalkyl, aryloxyalkylcycloalkyl, cycloalkenyl, oxacycloalkyl, or wherein any two of R₁, R₂,and R₃ form a ring containing 5 to 15 carbon atoms, and wherein any ofR₄, R₂, or R₃ optionally contain one oxygen-functional group selectedfrom carbonyl or protected form thereof, with the proviso that: a) whereR₂═R₃═H, R₁ cannot be methyl or H, b) where R₁═R₂═H, R₃ cannot be methylor ethyl, c) where R₃═H, and R₁ and R₂ form a cyclohexane or norbornenering, at least one additional carbon atom, oxygen atom, or double bondmust be present in the structure of R₁ or R₂.
 14. A compositioncomprising a base material and an amount of a compound according toclaim 13 effective to impart a fragrance or a flavor to the basematerial.
 15. A method of imparting a fragrance or a flavor to a basematerial comprising combining the base material with an effective amountof a compound according to claim 13.